Indole compounds

ABSTRACT

Indole compounds of the formula:  
                 
 
     wherein L 1  is CO; L 2  is a bond; R 1  is aryl or heteroaryl; R 2  is H, aryl, heteroaryl, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO 2 R, SO 3 R, SO 2 NRR′, SR, NRR′, NRSO 2 NR′R″, NRSO 2 R′, NRSO 3 R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)OR, or C(O)NRR′; each of R a , R b , R c , and R d , independently, is R, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO 2 R, SO 3 R, SO 2 NRR′, SR, NRR′, NRSO 2 NR′R″, NRSO 2 R′, NRSO 3 R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′, or R b  and R c , R a  and R b , or R c  and R d  taken together are O(CH 2 ) n O; and R c  is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO 2 R, SO 3 R, SO 2 NRR′, SR, NRR′, NRSO 2 NR′R″, NRSO 2 R′, NRSO 3 R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′; in which each of R, R′, and R″, independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4, or 5.

RELATED APPLICATION

[0001] This application claims priority to U.S. provisional applicationNo. 60/340,317, filed on Dec. 13, 2001, the contents of which areincorporated herein by reference.

BACKGROUND

[0002] Cancer treatment can be approached by several modes of therapy,including surgery, radiation, chemotherapy, or a combination of any ofthese treatments. Among them, chemotherapy is indispensable forinoperable or metastatic forms of cancer.

[0003] The microtubule system of eukaryotic cells is an important targetfor developing anti-cancer agents. More specifically, tubulinpolymerization/depolymerization is a popular target for newchemotherapeutic agents. A variety of clinically used compounds (e.g.,paclitaxel, epothilone A, vinblastine, combretastatin A-4, dolastatin10, and colchicine) target tubulin polymerization/depolymerization anddisrupt cellular microtubule structures, resulting in mitotic arrest andinhibition of the growth of new vascular epithelial cells. See, e.g.,Jordan et al. (1998) Med. Res. Rev. 18: 259-296. Thus, those compoundsmay have the ability to inhibit excessive angiogenesis, which occurs indiseases such as cancer (both solid and hematologic tumors),cardiovascular diseases (e.g., atherosclerosis), chronic inflammation(e.g., rheutatoid arthritis or Crohn's disease), diabetes (e.g.,diabetic retinopathy), macular degeneration, psoriasis, endometriosis,and ocular disorders (e.g., corneal or retinal neovascularization). See,e.g., Griggs et al. (2002) Am. J. Pathol. 160(3): 1097-103.

[0004] Take combretastatin A-4 (CA-4) for example. CA-4, isolated byPettit and co-workers in 1982 (Can. J. Chem. 60: 1374-1376), is one ofthe most potent anti-mitotic agents derived from the stem wood of theSouth African tree Combretum caffrum. This agent shows strongcytotoxicity against a wide variety of human cancer cells, includingmulti-drug resistant cancer cells. See, e.g., Pettit et al. (1995) J.Med. Chem. 38: 1666-1672; Lin et al. (1989) Biochemistry 28: 6984-6991;and Lin et al. (1988) Mol. Pharmacol. 34: 200-208. CA-4, structurallysimilar to colchicines, possesses a higher affinity for the colchicinebinding site on tubulin than colchicine itself. Pettit et al. (1989)Experientia 45: 209-211. It also has been shown to possessanti-angiogenesis activity. See Pinney et al. WO 01/68654A2. The lowwater-solubility of CA-4 limits its efficacy in vivo. See, e.g., Chaplinet al. (1999) Anticancer Research 19: 189-195; and Grosios et al. (1999)Br. J. Cancer 81: 1318-1327.

[0005] Identification of compounds that also target the microtubulesystem (e.g., tubulin polymerization/depolymerization) can lead to newtherapeutics useful in treating or preventing cancer or symptomsassociated with cancer.

SUMMARY

[0006] This invention is based on the discovery that indole compoundshave anti-cancer activities, and function via targeting the microtubulesystem (e.g., tubulin polymerization/depolymerization) or others.

[0007] In one aspect, this invention features indole compounds of thefollowing formula:

[0008] wherein L₁ is C(O); L₂ is a bond; R₁ is aryl or heteroaryl; R₂ isH, aryl, heteroaryl, halogen, nitro, nitroso, cyano, azide,isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR,NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)OR, or C(O)NRR′; each of R_(a), R_(b), R_(c), andR_(d), independently, is R, halogen, nitro, nitroso, cyano, azide,isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR,NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′, or R_(b) and R_(c), R_(a) andR_(b), or R_(c) and R_(d) taken together are O(CH₂)_(n)O; and R_(c) isH, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, halogen, nitro,nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′,SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′,NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′; inwhich each of R, R′, and R″, independently, is H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4,or 5. Note that the left atom shown in any substituted group describedabove is closest to the indole ring. Also note that when R_(a), R_(b),R_(c), and R_(d) are R, the just-described indole compounds may havedifferent R moieties. The same rule applies to other similar situations.

[0009] Referring to the just-described indole compounds, a subset ofthese compounds is featured by that R_(e) is H or alkyl. In thesecompounds, each of R_(a), R_(b), R_(c), and R_(d), independently, can beH, alkyloxy, alkyl, or halogen (e.g., R_(c) is alkyloxy, alkyl, orhalogen, and each of R_(a), R_(b), and R_(d) is H). R₁ can be3,4,5-trimethoxylphenyl. In some embodiments, one, two, or three ofR_(a), R_(b), R_(c), and R_(d) are alkyloxy, alkyl, or halogen.Preferably, one of R_(a), R_(b), R_(c), and R_(d) is alkyloxy, alkyl, orhalogen, and the others are H. More preferably, R_(c) is alkyloxy,alkyl, or halogen (e.g., R_(c) is OCH₃, OCH₂CH₃, CH₃, F, or Br), andeach of R_(a), R_(b), and R_(d) is H. R₂ can be H, OR, C(O)NRR′, C(O)OR(e.g., C(O)OC(CH₃)₃, or C(O)OC₆H₅), or SO₂R (e.g., SO₂CH₃, orSO₂(4-CO₂H—C₆H₄)). In other embodiments, R_(b) and R_(c) taken togetherare O(CH₂)_(n)O, and each of R_(a) and R_(d) is H, in which n is 1 or 2.Another subset of the indole compounds are those compounds wherein R₁ is5, 6, or 7-member aryl or heteroaryl tri-substituted with alkyloxy(e.g., 3,4,5-trimethoxylphenyl).

[0010] In another aspect, this invention features indole compounds ofthe formula above, wherein L₁ is C(O); L₂ is a bond; R₁ is aryl orheteroaryl; R₂ is alkyl, alkenyl, alkynyl, cyclyl, or heterocyclyl; eachof R_(a), R_(b), R_(c), and R_(d), independently, is R, halogen, nitro,isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR,NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′, or R_(b) and R_(c), R_(a) andR_(b), or R_(c), and R_(d) taken together are O(CH₂)_(n)O; and R_(e) isH, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl,halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,or C(O)NRR′; in which each of R, R′, and R″, independently, is H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; and n is 1,2, 3, 4, or 5.

[0011] Referring to the just-described indole compounds, a subset ofthese compounds is featured by that R_(e) is H or alkyl. In thesecompounds, each of R_(a), R_(b), R_(c), and R_(d), independently, can beH, alkyloxy, alkyl, or halogen (e.g., R_(c) is alkyloxy, alkyl, orhalogen, and each of R_(a), R_(b), and R_(d) is H). R₁ can be3,4,5-trimethoxylphenyl. In some embodiments, one, two, or three ofR_(a), R_(b), R_(c), and R_(d) are alkyloxy, alkyl, or halogen.Preferably, one of R_(a), R_(b), R_(c), and R_(d) is alkyloxy, alkyl, orhalogen, and the others are H. More preferably, R_(c) is alkyloxy,alkyl, or halogen (e.g., R_(c) is OCH₃), and each of R_(a), R_(b), andR_(d) is H. R₂ can be alkyl, alkenyl, or alkynyl (e.g., CH₃, C₂H₅,CH₂CH═CH₂, CH₂C≡CH, or CH₂-4-pyridinyl). In other embodiments, R_(b) andR_(c) taken together are O(CH₂)_(n)O, and each of R_(a) and R_(d) is H,in which n is 1 or 2. Another subset of the indole compounds are thosecompounds wherein R₁ is 5, 6, or 7-member aryl or heteroaryltri-substituted with alkyloxy (e.g., 3,4,5-trimethoxylphenyl).

[0012] In still another aspect, this invention features indole compoundsof the formula above, wherein L₁ is C(O); L₂ is a bond; R₁ is aryl orheteroaryl; R₂ is COR′″; each of R_(a), R_(b), R_(c), and R_(d),independently, is R, halogen, nitro, nitroso, cyano, azide,isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR,NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′, or R_(b) and R_(c), R_(a) andR_(b), or R_(c) and R_(d) taken together are O(CH₂)_(n)O; and R_(e) isR, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,or C(O)NRR′; in which each of R, R′, and R″ independently, is H, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; R′″ is H,alkyl, alkenyl, alkynyl, heteroaryl, cyclyl, or heterocyclyl; and n is1, 2, 3, 4, or 5.

[0013] Referring to the just-described indole compounds, a subset ofthese compounds is featured by that R_(e) is H or alkyl. In thesecompounds, each of R_(a), R_(b), R_(c), and R_(d), independently, can beH, alkyloxy, alkyl, or halogen (e.g., R_(c) is alkyloxy, alkyl, orhalogen, and each of R_(a), R_(b), and R_(d) is H). R₁ can be3,4,5-trimethoxylphenyl. In some embodiments, one, two, or three ofR_(a), R_(b), R_(c), and R_(d) are alkyloxy, alkyl, or halogen.Preferably, one of R_(a), R_(b), R_(c), and R_(d) is alkyloxy, alkyl, orhalogen, and the others are H. More preferably, R_(c) is alkyloxy,alkyl, or halogen (e.g., R_(c) is OCH₃), and each of R_(a), R_(b), andR_(d) is H. R′″ is alkyl (e.g., CH₂NRR′), alkenyl (e.g.,(E)—CH═CH—C₆H₅), or heteroaryl (e.g., 2-pyridinyl, 3-pyridinyl, 2-furyl,or 2-thienyl). In other embodiments, R_(b) and R_(c) taken together areO(CH₂)_(n)O, and each of R_(a) and R_(d) is H, in which n is 1 or 2.Another subset of the indole compounds are those compounds wherein R₁ is5, 6, or 7-member aryl or heteroaryl tri-substituted with alkyloxy(e.g., 3,4,5-trimethoxylphenyl).

[0014] In a further aspect, this invention features indole compounds ofthe formula above, L₁ is a bond; L₂ is C(O); R₁ is H, alkenyl, alkynyl,aryl, heteroaryl, cyclyl, heterocyclyl, halogen, nitro, nitroso, cyano,azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R,SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″,NRC(O)OR′, NRC(N)NR′R″, C(O)OR, or C(O)NRR′; R₂ is aryl or heteroaryl;each of R_(a), R_(b), R_(c), and R_(d), independently, is H,unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl,heterocyclyl, halogen, nitro, nitroso, cyano, azide, isothionitro, OR,OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″,NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R,C(O)OR, C(O)NRR′, or R_(b) and R_(c), R_(a) and R_(b), or R_(c) andR_(d) taken together are O(CH₂)_(n)O; and R_(e) is H, alkyl, alkenyl,alkynyl, cyclyl, heterocyclyl, heteroaryl, halogen, nitro, nitroso,cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R,SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″,NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′; in which each of R,R′, and R″ independently, is H, alkyl, alkenyl, alkynyl, aryl,heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4, or 5.

[0015] Referring to the just-described indole compounds, a subset ofthese compounds is featured by that R_(e) is H or alkyl. In thesecompounds, each of R_(a), R_(b), R_(c), and R_(d), independently, can beH, alkyloxy, alkyl, or halogen (e.g., R_(b) is alkyloxy, alkyl, orhalogen, and each of R_(a), R_(c), and R_(d) is H). R₂ can be3,4,5-trimethoxylphenyl or 3,5-dimethoxylphenyl. In some embodiments,one, two, or three of R_(a), R_(b), R_(c), and R_(d) are alkyloxy,alkyl, or halogen. Preferably, one of R_(a), R_(b), R_(c), and R_(d) isalkyloxy, alkyl, or halogen, and the others are H. More preferably,R_(b) is alkyloxy, alkyl, or halogen (e.g., R_(b) is OCH₃), and each ofR_(a), R_(c), and R_(d) is H. R₁ can be H or alkyl. In otherembodiments, R_(b) and R_(c) taken together are O(CH₂)_(n)O, and each ofR_(a) and R_(d) is H, in which n is 1 or 2. Another subset of the indolecompounds are those compounds wherein R₂ is 5, 6, or 7-member aryl orheteroaryl tri-substituted with alkyloxy (e.g.,3,4,5-trimethoxylphenyl).

[0016] In another aspect, this invention features indole compounds ofthe formula above, wherein L₁ is O, S, NR, SO₂, or CH₂; L₂ is a bond; R₁is 5, 6, or 7-member aryl or heteroaryl tri-substituted with alkyloxy;and each of R₂, R_(a), R_(b), R_(c), R_(d), and R_(e), independently, R,halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′, or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) takentogether are O(CH₂)_(n)O; in which each of R, R′, and R″, independently,is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, orheterocyclyl; and n is 1, 2, 3, 4, or 5.

[0017] Referring to the just-described indole compounds, a subset ofthese compounds is featured by R_(e) is H or alkyl. In these compounds,each of R_(a), R_(b), R_(c), and R_(d), independently, can be H,alkyloxy, alkyl, or halogen (e.g., R_(c) is alkyloxy, alkyl, or halogen,and each of R_(a), R_(b), and R_(d) is H). R₁ can be3,4,5-trimethoxylphenyl. In some embodiments, one, two, or three ofR_(a), R_(b), R_(c), and R_(d) are alkyloxy, alkyl, or halogen.Preferably, one of R_(a), R_(b), R_(c), and R_(d) is alkyloxy, alkyl, orhalogen, and the others are H. More preferably, R_(c) is alkyloxy,alkyl, or halogen (e.g., R_(c) is OCH₃ or CH₃), and each of R_(a),R_(b), and R_(d) is H. In other embodiments, R_(b) and R_(c) takentogether are O(CH₂)_(n)O, and each of R_(a) and R_(d) is H, in which nis 1 or 2. Another subset of the indole compounds are those compoundswherein R₁ is 5, 6, or 7-member aryl or heteroaryl tri-substituted withalkyloxy (e.g., 3,4,5-trimethoxylphenyl).

[0018] Further, in still another aspect, this invention features indolecompounds of the formula above, wherein L₁ is a bond; L₂ is O, S, NR,SO₂, or CH₂; R₂ is 5, 6, or 7-member aryl or heteroaryl tri-substitutedwith alkyloxy; and each of R₁, R_(a), R_(b), R_(c), R_(d), and R_(e),independently, R, halogen, nitro, nitroso, cyano, azide, isothionitro,OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′,NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′, or R_(b) and R_(c), R_(a) andR_(b), or R_(c) and R_(d) taken together are O(CH₂)_(n)O; in which eachof R, R′, and R″, independently, is H, alkyl, alkenyl, alkynyl, aryl,heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4, or 5.

[0019] Referring to the just-described indole compounds, a subset ofthese compounds is featured by R_(e) is H or alkyl. In these compounds,each of R_(a), R_(b), R_(c), and R_(d), independently, can be H,alkyloxy, alkyl, or halogen (e.g., R_(b) is alkyloxy, alkyl, or halogen,and each of R_(a), R_(c), and R_(d) is H). R₂ can be3,4,5-trimethoxylphenyl. In some embodiments, one, two, or three ofR_(a), R_(b), R_(c), and R_(d) are alkyloxy, alkyl, or halogen.Preferably, one of R_(a), R_(b), R_(c), and R_(d) is alkyloxy, alkyl, orhalogen, and the others are H. More preferably, R_(b) is alkyloxy,alkyl, or halogen (e.g., R_(b) is OCH₃ or CH₃), and each of R_(a),R_(c), and R_(d) is H. In other embodiments, R_(b) and R_(c) takentogether are O(CH₂)_(n)O, and each of R_(a) and R_(d) is H, in which nis 1 or 2. Another subset of the indole compounds are those compoundswherein R₂ is 5, 6, or 7-member aryl or heteroaryl tri-substituted withalkyloxy (e.g., 3,4,5-trimethoxylphenyl).

[0020] This invention also features indole compounds of the formulaabove, wherein L₁ is O, S, NR, SO₂, or CH₂; L₂ is a bond; R₁ is 5, 6, or7-member aryl or heteroaryl di-substituted with alkyloxy; and each ofR₂, R_(a), R_(b), R_(c), R_(d), and R_(e), independently, R, halogen,nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR,OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′,NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′,or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) taken togetherare O(CH₂)_(n)O; in which each of R, R′, and R″, independently, is H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; andn is 1, 2, 3, 4, or 5. In the just-described indole compounds, R₁ can be3,5-dimethoxylphenyl.

[0021] Also within the scope of this invention are indole compounds ofthe formula above, wherein L₁ is a bond; L₂ is O, S, NR, SO₂, or CH₂; R₂is 5, 6, or 7-member aryl or heteroaryl di-substituted with alkyloxy;and each of R₁, R_(a), R_(b), R_(c), R_(d), and R_(e), independently, R,halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′, or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) takentogether are O(CH₂)_(n)O in which each of R, R′, and R″, independently,is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, orheterocyclyl; and n is 1, 2, 3, 4, or 5. In the just-described indolecompounds, R₂ can be 3,5-dimethoxylphenyl.

[0022] Unless specifically pointed out, alkyl, alkenyl, alkynyl, aryl,heteroaryl, cyclyl, and heterocyclyl mentioned herein include bothsubstituted and unsubstituted moieties. The term “substituted” refers toone or more substituents (which may be the same or different), eachreplacing a hydrogen atom. Examples of substituents include, but are notlimited to, halogen, cyano, nitro, hydroxyl, amino, mercapto, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, alkyloxy,aryloxy, alksulfanyl, arylsulfanyl, alkylamino, arylamino, dialkylamino,diarylamino, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkylcarboxyl, arylcarboxyl, heteroarylcarboxyl, alkyloxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbamido, arylcarbamido,heterocarbamido, alkylcarbamyl, arylcarbamyl, heterocarbamyl, whereineach of alkyl (including alk), alkenyl, aryl, heteroaryl, cyclyl, andheterocyclyl is optionally substituted with halogen, cyano, nitro,hydroxyl, amino, mercapto, alkyl, aryl, heteroaryl, alkyloxy, aryloxy,alkylcarbonyl, arylcarbonyl, alkylcarboxyl, arylcarboxyl,alkyloxycarbonyl, or aryloxycarbonyl.

[0023] As used herein, the term “alkyl” refers to a straight-chained orbranched alkyl group containing 1 to 6 carbon atoms. Examples of alkylgroups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, andn-pentyl. Similarly, the term “alkenyl” or “alkynyl” refers to astraight-chained or branched alkenyl or alkynyl group containing 2 to 6carbon atoms.

[0024] The term “aryl” refers to a hydrocarbon ring system (mono-cyclicor bi-cyclic) having at least one aromatic ring. Examples of arylmoieties include, but are not limited to, phenyl, naphthyl, and pyrenyl.

[0025] The term “heteroaryl” refers to a hydrocarbon ring system(mono-cyclic or bi-cyclic) having at least one aromatic ring whichcontains at least one heteroatom such as O, N, or S as part of the ringsystem and the reminder being carbon. Examples of heteroaryl moietiesinclude, but are not limited to, furyl, pyrrolyl, thienyl, oxazolyl,imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, andindolyl.

[0026] The terms “cyclyl” and “heterocyclyl” refer to a partially orfully saturated mono-cyclic or bi-cyclic ring system having from 4 to 14ring atoms. A heterocyclyl ring contains one or more heteroatoms (e.g.,O, N, or S) as part of the ring system and the remainder being carbon.Exemplary cyclyl and heterocyclyl rings are cyclohexane, piperidine,piperazine, morpholine, thiomorpholine, and 1,4-oxazepane.

[0027] Set forth below are exemplary compounds of this invention:

[0028] (6-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 1);

[0029] (6-Methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 2);

[0030](6-Methoxy-1-pyridin-4-ylmethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 3);

[0031](1-Allyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 4);

[0032][6-Methoxy-1-(pyridine-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 5);

[0033] 6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acidtert-butyl ester (Compound 6);

[0034](1-Methanesulfonyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 7);

[0035][6-Methoxy-1-(morpholine-4-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 8);

[0036][6-Methoxy-1-(2-piperidin-1-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 9);

[0037](6-Methoxy-1-prop-2-ynyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 10);

[0038] 6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic aciddimethylamide (Compound 11);

[0039]1-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-3-phenyl-propenone(Compound 12);

[0040] 6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acidphenyl ester (Compound 13);

[0041][1-(5-Dimethylamino-naphthalene-1-sulfonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 14);

[0042][1-(2-Dimethylamino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 15);

[0043](6-Methoxy-1-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 16);

[0044][1-(2-Amino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 17);

[0045][1-(Furan-2-carbonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 18);

[0046](1-Ethyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 19);

[0047][6-Methoxy-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 20);

[0048][1-(4-Chloro-benzyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 21);

[0049](1-Benzyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 22);

[0050] (6-Fluoro-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 23);

[0051] (6-Bromo-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 24);

[0052](4,5,6-Trimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 25);

[0053] 6-Methoxy-3-(3,4,5-trimethoxy-benzyl)-1H-indole (Compound 26);

[0054] (5-Methoxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 27);

[0055] (6-Fluoro-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 28);

[0056] (5,6-Dimethoxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 29);

[0057](5,6-Bis-benzyloxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 30);

[0058] [1,3]Dioxolo[4,5-f]indol-5-yl-(3,4,5-trimethoxy-phenyl)-methanone(Compound 31);

[0059][3-(2-Dimethylamino-ethyl)-5-methoxy-indol-1-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 32);

[0060]N-{2-[5-Methoxy-1-(3,4,5-trimethoxy-benzoyl)-1H-indol-3-yl]-ethyl}-acetamide(Compound 33);

[0061] (5,6-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 34);

[0062](5-Methoxy-2-methyl-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 35);

[0063] (1,6-Dimethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 36);

[0064](1-Ethyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 37);

[0065](1-Allyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 38);(5-Ethyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 39);

[0066](5-Methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 40);

[0067](5-Allyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 41);

[0068](6-Methoxy-2-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 42);

[0069] 6-Methoxy-3-(3,4,5-trimethoxy-phenylsulfanyl)-1H-indole (Compound43);

[0070] (6-Ethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 44);

[0071] (7-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 45);

[0072] (4-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 46);

[0073](5-Methoxy-4-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 47);

[0074] (4,7-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 48);

[0075] (4,6-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 49);

[0076] (5,7-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 50);

[0077]{6-Methoxy-1-[4-(4-nitro-phenyl)-furan-2-ylmethyl]-1H-indol-3-yl}-(3,4,5-trimethoxy-phenyl)-methanone(Compound 51);

[0078] (6-Hydroxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 52);

[0079] 6-Methoxy-3-(3,4,5-trimethoxy-benzenesulfonyl)-1H-indole(Compound 53);

[0080][1-(2-Dimethylamino-ethyl)-4,5,6-trimethoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 54),

[0081]4-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-sulfonyl]-benzoicacid (Compound 55);

[0082](5H-[1,3]Dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 56)

[0083]{2-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-2-oxo-ethyl}-carbamicacid 9H-fluoren-9-yl-methyl ester (Compound 57);

[0084][6-Methoxy-1-(pyridine-3-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 58);

[0085][6-Methoxy-1-(thiophene-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone(Compound 59);

[0086] (5-Methyl-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 60; and

[0087] (3,5-Dimethoxy-phenyl)-(5-methoxy-indol-1-yl)-methanone (Compound61).

[0088] Another aspect of the present invention relates to apharmaceutical composition that contains a pharmaceutically acceptablecarrier and an effective amount of at least one of the indole compoundsdescribed above.

[0089] A further aspect of this invention relates to a method fortreating cancer, e.g., carcinoma or sarcoma. The method includesadministering to a subject (e.g., a human or animal) in need thereof aneffective amount of an indole compound of the formula above, whereineach of L₁ and L₂, independently, is a bond, CO, O, S, NR, SO₂, or CH₂;in which if one of L₁ and L₂ is a bond, the other one is CO, O, S, NR,SO₂, or CH₂; each of R₁ and R₂, independently, is R, halogen, nitro,nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′,SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′,NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′; each ofR_(a), R_(b), R_(c), R_(d) and R_(e), independently, R, halogen, nitro,nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′,SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′,NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′, or R_(b)and R_(c), R_(a) and R_(b), or R_(c) and R_(d) taken together areO(CH₂)_(n)O; and in which each of R, R′, and R″, independently, is H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; andn is 1, 2, 3, 4, or 5.

[0090] In still another aspect, this invention features a method forinhibiting tubulin polymerization. The method includes administering toa subject (e.g., a human or animal) in need thereof an effective amountof one or more of the just described indole compounds.

[0091] In yet another aspect, this invention features a method fortreating an angiogenesis-related disorder. The method includesadministering to a subject (e.g., a human or animal) in need thereof aneffective amount of one or more of the just described indole compounds.

[0092] This invention also includes a method for inhibiting cellularproliferation or inducing the killing of hyperproliferation cells. Themethod involves treatment of a disorder characterized by aberrantcellular proliferation or differentiation in a subject (e.g., a human oranimal). The method comprises administering to the subject an effectiveamount of one or more the just described indole compounds.

[0093] The methods described above can also include the step ofidentifying that the subject is in need of treatment of diseases ordisorders described above. The identification can be in the judgment ofa subject or a health professional and can be subjective (e.g., opinion)or objective (e.g., measurable by a test or a diagnostic method).

[0094] All of the indole compounds described above include the compoundsthemselves, as well as their salts and their prodrugs, if applicable.The salts, for example, can be formed between a positively chargedsubstituent (e.g., amino) on a compound and an anion. Suitable anionsinclude, but are not limited to, chloride, bromide, iodide, sulfate,nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, andacetate. Likewise, a negatively charged substituent (e.g., carboxylate)on a compound can form a salt with a cation. Suitable cations include,but are not limited to, sodium ion, potassium ion, magnesium ion,calcium ion, and an ammonium cation such as teteramethylammonium ion.Examples of prodrugs include esters and other pharmaceuticallyacceptable derivatives, which, upon administration to a subject, arecapable of providing the indole compounds described above (see Goodmanand Gilman's, The Pharmacological basis of Therapeutics, 8^(th) ed.,McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”).

[0095] In addition, some of the just-described indole compounds have oneor more double bonds, or one or more asymmetric centers. Such compoundscan occur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double bond isomeric forms.

[0096] Further, the aforementioned indole compounds also include theirN-oxides. The term “N-oxides” refers to one or more nitrogen atoms, whenpresent in an indole compound, are in N-oxide form, i.e., N→O.

[0097] Combinations of substituents and variables envisioned by thisinvention are only those that result in the formation of stable indolecompounds without departing from the spirit and scope thereof. The term“stable”, as used herein, refers to compounds which possess stabilitysufficient to allow manufacture and which maintains the integrity of thecompound for a sufficient period of time to be useful for the purposesdetailed herein (e.g., treating cancer).

[0098] Also within the scope of this invention are a compositioncontaining one or more of the indole compounds described above for usein treating diseases or disorders described above, and the use of such acomposition for the manufacture of a medicament for the aforementionedtreatment.

[0099] Other features or advantages of the present invention will beapparent from the following detailed description of several embodiments,and also from the appending claims.

DETAILED DESCRIPTION

[0100] The indole compounds described above can be prepared by methodswell known in the art, as well as by the synthetic routes disclosedherein. For example, as shown in Scheme 1 below, one can couple anindole compound with an acyl chloride. The 6-position of the startingindole compound can be alkyloxy, e.g., OCH₃. The 2, 4, 5, and7-positions of the starting indole may be substituted. The product ofthe coupling reaction, referred to simply as an“indol-3-yl-aryl-methanone” for brevity, can be converted to a1-substituted-indol-3-yl-aryl-methanone by coupling theindol-3-yl-aryl-methanone with a halide, e.g., R_(e)COCl, R_(e)CH₂Cl, orR_(e)SO₂Cl. Alternatively, the indol-3-yl-aryl-methanone can be reducedto an indol-3-yl-aryl-methane, which can be further reacted with ahalide to produce a 1-substituted, indol-3-yl-aryl-methane. Once again,although the 2, 4, 5, and 7-positions of the starting indole compoundmay be substituted, the compounds are referred to as1-substituted-indol-3-yl-aryl-methane for brevity.

[0101] In another example, as shown in Scheme 2 below, one can couple anindole compound with an acyl chloride in the presence of a base (e.g.,NaO^(t)Bu). The 5-position of the starting indole can be alkyloxy, e.g.,OCH₃. The 2, 4, 6, and 7-positions of the indole may be H, orsubstituted. The coupling reaction produces an indol-1-yl-aryl-methanoneof interest. The product of the coupling reaction can be reduced to anindol-1-yl-aryl-methane.

[0102] If preferred, indole compounds having other types of L₁ or L₂ canbe prepared by similar coupling reactions. See the specific examplesbelow

[0103] The chemicals used in the above-described synthetic routes mayinclude, for example, solvents, reagents, catalysts, and protectinggroup and deprotecting group reagents. The methods described above mayalso additionally include steps, either before or after the stepsdescribed specifically herein, to add or remove suitable protectinggroups in order to ultimately allow synthesis of the indole compounds.In addition, various synthetic steps may be performed in an alternatesequence or order to give the desired compounds. Synthetic chemistrytransformations and protecting group methodologies (protection anddeprotection) useful in synthesizing applicable indole compounds areknown in the art and include, for example, those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and subsequent editions thereof.

[0104] Details of synthesis of Compounds 1-54 of this invention aredescribed in Examples 1-54, respectively.

[0105] An indole compound thus obtained can be further purified by flashcolumn chromatography, high performance liquid chromatography, orcrystallization.

[0106] Also within the scope of this invention is a pharmaceuticalcomposition that contains an effective amount of at least one indolecompound of the present invention and a pharmaceutically acceptablecarrier. Further, this invention covers a method of administering to asubject in need of treating cancer an effective amount of an indolecompounds described in the “Summary” section. Included in this inventionare a method for inhibiting tubulin polymerization, a method fortreating an angiogenesis-related disorder, and a method for inhibitingcellular proliferation or inducing the killing of hyperproliferationcells. Each of these methods includes administering to a subject in needthereof an effective amount of the aforementioned indole compounds.

[0107] As used herein, the term “treating” or “treatment” is defined asthe application or administration of a composition including an indolecompound to a subject, who has a disorder (e.g., cancer), a symptom ofthe disorder, a disease or disorder secondary to the disorder, or apredisposition toward the disorder, with the purpose to cure, alleviate,relieve, remedy, or ameliorate the disorder, the symptom of thedisorder, the disease or disorder secondary to the disorder, or thepredisposition toward the disorder. “An effective amount” refers to anamount of an indole compound which confers a therapeutic effect on thetreated subject. The therapeutic effect may be objective (i.e.,measurably by some tests or markers) or subjective (i.e., a subjectgives an indication of or feels an effect). The interrelationship ofdosages for animals and humans (based on milligrams per meter squared ofbody surface) is described in Freireich et al., (1966) Cancer ChemotherRep 50: 219. Body surface area may be approximately determined fromheight and weight of the patient. See, e.g., Scientific Tables, GeigyPharmaceuticals, Ardley, N.Y., 1970, 537. An effective amount of theindole compounds can range from about 0.1 mg/Kg to about 1000 mg/Kg.Effective doses will also vary, as recognized by those skilled in theart, depending on the types of tumors treated, route of administration,excipient usage, and the possibility of co-usage with other therapeutictreatments such as use of other anti-cancer agents or radiation therapy.Examples of the other anti-cancer agents are paclitaxel, docitaxel,doxorubicin, daunorubicin, epirubicin, fluorouracil, melphalan,cis-platin, carboplatin, cyclophosphamide, mitomycin C, methotrexate,mitoxantrone, vinblastine, vincristine, ifosfamide, teniposide,etoposide, bleomycin, leucovorin, cytarabine, dactinomycin, interferonalpha, streptozocin, prednisolone, procarbazine, irinotecan, topotecan,colony stimulating factor, granulocyte macrophage colony stimulatingfactor, 1,3-bis-2-chloroethyl-1-nitroso-urea, and imatinib mesylate.

[0108] As used herein, the terms “cancer” and “hyperproliferative” referto cells having the capacity for autonomous growth, i.e., an abnormalstate or condition characterized by rapidly proliferating cell growth.Hyperproliferative disease states may be categorized as pathologic,i.e., characterizing or constituting a disease state, or may becategorized as non-pathologic, i.e., a deviation from normal but notassociated with a disease state. The term is meant to include all typesof cancerous growths or oncogenic processes, metastatic tissues ormalignantly transformed cells, tissues, or organs, irrespective ofhistopathologic type or stage of invasiveness. “Pathologichyperproliferative” cells occur in disease states characterized bymalignant tumor growth. Examples of non-pathologic hyperproliferativecells include proliferation of cells associated with wound repair.

[0109] Examples of cellular proliferative and/or differentiativedisorders include cancer, e.g., carcinoma, sarcoma, or metastaticdisorders. The indole compounds described above are useful for thetreatment of disease caused or exascerbated by cell proliferation. Ascell proliferation inhibitors, these compounds are useful in thetreatment of both primary and metastatic solid tumors and carcinomas ofthe breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus,stomach, pancreas, liver, gallbladder, bile ducts, small intestine,urinary tract including kidney, bladder and urothelium, female genitaltract including cervix, uterus, ovaries, choriocarcinoma, andgestational trophoblastic disease, male genital tract includingprostate, seminal vesicles, testes, and germ cell tumors, endocrineglands including thyroid, adrenal, and pituitary, skin includinghemangiomas, melanomas, sarcomas arising from bone or soft tissuesincluding Kaposi's sarcoma, tumors of the brain, nerves, and eyes,meninges including astrocytomas, gliomas, glioblastomas,retinoblastomas, neuromas, neuroblastomas, Schwannomas and meningiomas,solid tumors arising from hematopoietic malignancies including leukemiasand chloromas, plasmacytomas, plaques, tumors of mycosis fungoides,cutaneous T-cell lymphoma/leukemia, lymphomas including Hodgkin's andnon-Hodgkin's lymphomas, prophylaxis of autoimmune diseases includingrheumatoid, immune and degenerative arthritis, ocular diseases includingdiabetic retinopathy, retinopathy of prematurity, corneal graftrejection, retrolental fibroplasia, neovascular glaucoma, rubeosis,retinal neovascularization due to macular degeneration, hypoxia,abnormal neovascularization conditions of the eye, skin diseasesincluding psoriasis, blood vessel diseases including hemagiomas andcapillary proliferation within atherosclerotic plaques, Osler-WebberSyndrome, myocardial angiogenesis, plaque neovascularization,telangiectasia, hemophiliac joints, angiofibroma, and wound granulation.In addition, cancer can be a drug resistance phenotype wherein cancercells express P-glycoprotein, multidrug resistance-associated proteins,lung cancer resistance-associated proteins, breast cancer resistanceproteins, or other proteins associated with resistance to anti-cancerdrugs.

[0110] The term “angiogenesis” refers to the growth of new bloodvessels—an important natural process occurring in the body. In manyserious diseases states, the body loses control over angiogenesis.Angiogenesis-dependent diseases result when new blood vessels growexcessively. Examples of angiogenesis-related disorders includecardiovascular diseases (e.g., atherosclerosis), chronic inflammation(e.g., rheutatoid arthritis or Crohn's disease), diabetes (e.g.,diabetic retinopathy), macular degeneration, psoriasis, endometriosis,and ocular disorders (e.g., corneal or retinal neovascularization).

[0111] To practice the method of the present invention, theabove-described pharmaceutical composition can be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

[0112] A sterile injectable composition, e.g., a sterile injectableaqueous or oleaginous suspension, can be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as Tween 80) and suspending agents. The sterile injectablepreparation can also be a sterile injectable solution or suspension in anon-toxic parenterally acceptable diluent or solvent, for example, as asolution in 1,3-butanediol. Among the acceptable vehicles and solventsthat can be employed are mamlitol, water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium (e.g.,synthetic mono- or diglycerides). Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions can also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agents.Other commonly used surfactants such as Tweens or Spans or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms can also be used for the purposes of formulation.

[0113] A composition for oral administration can be any orallyacceptable dosage form including, but not limited to, capsules, tablets,emulsions and aqueous suspensions, dispersions and solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions or emulsions are administered orally, the active ingredientcan be suspended or dissolved in an oily phase combined with emulsifyingor suspending agents. If desired, certain sweetening, flavoring, orcoloring agents can be added. A nasal aerosol or inhalation compositioncan be prepared according to techniques well-known in the art ofpharmaceutical formulation and can be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. An indolecompound-containing composition can also be administered in the form ofsuppositories for rectal administration.

[0114] The carrier in the pharmaceutical composition must be“acceptable” in the sense of being compatible with the active ingredientof the formulation (and preferably, capable of stabilizing it) and notdeleterious to the subject to be treated. For example, solubilizingagents such as cyclodextrins, which form specific, more solublecomplexes with the indole compounds, or one or more solubilizing agents,can be utilized as pharmaceutical excipients for delivery of the indolecompounds. Examples of other carriers include colloidal silicon dioxide,magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0115] The indole compounds can be preliminarily screened for theirefficacy in treating cancer by one or more of the following in vitroassays.

[0116] In one assay, an indole compound is tested for its cytotoxicityon MCF-7 cells (a breast carcinoma cell line). More specifically, cellsare incubated with a test compound for 24 hr. The cytotoxic effect canbe determined using the MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt) assay method described in Goodwin et al. (1995, J. Immunol.Methods. 179: 95-103). Cytotoxicity of the test compound is expressed interms of IC₅₀ values (i.e., the concentration of the test compound whichachieves a half-maximal inhibition of cell growth).

[0117] In another assay, an indole compound is tested for itscytotoxicity in cell cultures and polymerization of tubulin in theabsence of GTP. The cytotoxicity is determined using the turbidimetricassay of microtubule protein described by Lopes et al. (1997 CancerChemother. Pharmacol. 41: 37-47). Tubulin polymerization is monitoredspectrophotometrically by following changes in turbidity as a measure ofpolymer mass.

[0118] The anti-cancer activity of an indole compound can be furtherassessed using an in vivo animal model. See the specific example below.

[0119] Without further elaboration, it is believed that the abovedescription has adequately enabled the present invention. The followingspecific embodiments are, therefore, to be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever. All of the publications cited herein are herebyincorporated by reference in their entirety.

EXAMPLE 1 Synthesis of Compound 1:(6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0120]

[0121] To a mixture of 6-methoxyindole (0.3 g, 2.03 mmol) and anhydrousZnCl₂ (0.56 g, 4.07 mmol) in CH₂Cl₂ (10 mL), EtMgBr (0.9 ml, 3 M) wasadded over 10 min at room temperature. The obtained suspension wasstirred for 1 hr. To the suspension, the solution of3,4,5-trimethoxybenzoyl chloride/CH₂Cl₂ (10 ml) was added dropwiselyduring 5 min for a coupling reaction. The reaction mixture continuedstirring for another 1 hr and AlCl₃ (0.27 g, 2.03 mmol) was added. Theresultant thick mixture was vigorously stirred for 5 hr while monitoringby TLC (EtOAc:n-hexane=1:1). The reaction was quenched with H₂O (10 ml)and extracted with CH₂Cl₂ (10 mL×3). The combined extracts was dried byMgSO₄, and evaporated to give a brown oil which was chromatographed(silica gel; EtOAc:n-hexane=1:1) to afford Compound 1 (0.5 g, 72%) as awhite solid.

[0122]¹H NMR (CDCl₃), δ (ppm): 3.77 (s, 3H), 3.83 (s, 3H), 3.92 (s, 6H),6.85 (d, J=2.1 Hz, 1H), 6.93 (dd, J=8.9, 2.4 Hz, 1H), 7.08 (s, 2H), 7.59(s, 1H), 8.22 (d, J=8.7 Hz, 1H), 9.80 (br, 1H, NH).

[0123] MS (EI): m/z 342 (M+H).

EXAMPLE 2 Synthesis of Compound 2:(6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0124]

[0125] Compound 2 was prepared in a similar manner as described inExample 1.

[0126]¹H NMR (CDCl₃), δ (ppm): 2.45 (s, 3H), 3.85 (s, 6H), 3.92 (s, 6H),7.09 (s, 2H), 7.13 (dd, J=8.4, 0.9 Hz, 1H), 7.20 (d, J=0.6 Hz, 1H), 7.63(d, J=2.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 9.36 (br, 1H, NH).

[0127] MS (EI): m/z 326 (M+H).

EXAMPLE 3 Synthesis of Compound 3:(6-methoxy-1-pyridin-4-ylmethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0128]

[0129] To a stirred solution of Compound 1 (0.07 g, 0.20 mmol), NaOtBu(0.08 g, 0.82 mmol), and 4-picoyl chloride hydrochloride (0.06 g, 0.41mnol) in THF (10 mL) was heated to reflux. After 15 hr, the reactionmixture was evaporated, and the residue was extracted with CH₂Cl₂ (10mL×3). The combined extracts were dried by MgSO₄ and evaporated to givea yellow oil which was chromatographied by silica gel(EtOAc:n-hexane=2:1) to afford Compound 3 (0.10 g, 83%) as a whitesolid.

[0130]¹H NMR (CDCl₃), δ (ppm): 3.80 (s, 3H), 3.86 (s, 6H), 3.90 (s, 3H),5.42 (s, 2H), 6.64 (d, J=2.1 Hz, 1H), 7.00 (dd, J=8.7, 2.1 Hz, 1H), 7.08(s, 2H), 7.10-7.13 (m, 2H), 7.59 (s, 1H), 8.27 (d, J=9.0 Hz, 1H).

[0131] MS (EI): m/z 433 (M+H).

EXAMPLE 4 Synthesis of Compound 4:(1-allyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0132]

[0133] Compound 4 was prepared in a similar manner as described inExample 3.

[0134]¹H NMR (CDCl₃), δ (ppm): 3.85 (s, 3H), 3.87 (s, 6H), 3.90 (s, 3H),4.69-4.71 (m, 2H), 5.12-5.28 (m, 2H), 5.94-6.03 (m, 1H), 6.79 (d, J=2.4Hz, 1H), 6.95 (dd, J=8.7, 2.4 Hz, 1H), 7.07 (s, 2H), 7.51 (s, 1H), 8.23(d, J=8.7 Hz, 1H).

[0135] MS (EI): m/z 382 (M+H).

EXAMPLE 5 Synthesis of Compound 5:[6-methoxy-1-(pyridine-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0136]

[0137] To a solution of Compound 1 (0.1 g, 0.29 mmol) in THF (15 mL) wasadded NaOtBu (0.11 g, 1.17 mmol) in a portion and stirred at roomtemperature for 15 min. The resulting dark green mixture was addedpicolinoyl chloride hydrochloride (0.1 g, 0.58 mmol) and then keptstirring at room temperature. After 15 hr, the reaction mixture wasevaporated, and the residue was extracted with CH₂Cl₂ (10 mL×3). Thecombined extracts were dried by MgSO₄ and evaporated to get a yellow oilwhich was chromatographed by silica gel (EtOAc:n-hexane=1:1) to affordCompound 5 (0.11 g, 90%) as a white solid.

[0138]¹H NMR (CDCl₃), δ (ppm): 3.94 (s, 12H), 7.09 (dd, J=8.7, 2.4 Hz,1H), 7.24 (s, 2H), 7.53-7.58 (m, 1H), 7.95-8.00 (m, 1H), 8.16-8.19 (m,3H), 8.60 (s, 1H), 8.66-8.69 (m,1H).

[0139] MS (EI): m/z 455 (M+H).

EXAMPLE 6 Synthesis of Compound 6:6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acidtert-butyl ester

[0140]

[0141] Compound 6 was prepared in a similar manner as described inExample 5.

[0142]¹H NMR (CDCl₃), δ (ppm): 1.68 (s, 9H), 3.89 (s, 3H), 3.90 (s, 6H),3.94 (s, 3H), 7.00 (dd, J=8.9, 2.4 Hz, 1H), 7.15 (s, 2H), 7.73 (d, J=2.1Hz, 1H), 7.99 (s, 1H), 8.13 (d, J=8.7 Hz, 1H).

[0143] MS (EI): m/z 442 (M+H).

EXAMPLE 7 Synthesis of Compound 7:(1-methanesulfonyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0144]

[0145] Compound 7 was prepared in a similar manner as described inExample 5.

[0146]¹H NMR (CDCl₃), δ (ppm): 3.22 (s, 3H), 3.92 (s, 9H), 3.96 (s, 3H),7.09 (dd, J=9.0, 2.4 Hz, 1H), 7.14 (s, 2H), 7.43 (d, J=2.4 Hz, 1H), 7.84(s, 1H), 8.20 (d, J=9.0 Hz, 1H).

[0147] MS (EI): m/z 420 (M+H).

EXAMPLE 8 Synthesis of Compound 8:[6-methoxy-1-(morpholine-4-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0148]

[0149] Compound 8 was prepared in a similar manner as described inExample 5.

[0150]¹H NMR (CDCl₃), δ (ppm): 3.58-3.61 (m, 4H), 3.73-3.76 (m, 4H),3.87 (s, 9H), 3.92 (s, 3H), 6.98 (dd, J=8.9, 2.1 Hz, 1H), 7.10 (s, 2H),7.12 (d, J=2.1 Hz, 1H), 7.68 (s, 1H), 8.13 (d, J=9.0 Hz, 1H).

[0151] MS (EI): m/z 455 (M+H).

EXAMPLE 9 Synthesis of Compound 9:[6-methoxy-1-(2-piperidin-1-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0152]

[0153] Compound 9 was prepared in a similar manner as described inExample 3.

[0154]¹H NMR (CDCl₃), δ (ppm): 1.42-1.44 (m, 2H), 1.53-1.60 (m, 4H),2.44 (t, J=6.6 Hz, 2H), 3.88 (s, 9H), 3.91 (s, 3H), 4.22 (t, J=6.6 Hz,2H), 6.87 (d, J=2.1 Hz, 1H), 6.96 (dd, J=8.9, 2.1 Hz, 1H), 7.08 (s, 2H),7.60 (s, 1H), 8.23 (d, J=8.7 Hz, 1H).

[0155] MS (EI): m/z 453 (M+H).

EXAMPLE 10 Synthesis of Compound 10:(6-methoxy-1-prop-2-ynyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0156]

[0157] Compound 10 was prepared in a similar manner as described inExample 3.

[0158]¹H NMR (CDCl₃), δ (ppm): 3.88 (s, 9H), 3.93 (s, 3H), 5.66 (d,J=6.6 Hz, 2H), 6.95-7.16 (m, 5H), 7.58 (s, 1H), 8.20 (d, J=8.7 Hz, 1H).

[0159] MS (EI): m/z 380 (M+H).

EXAMPLE 11 Synthesis of Compound 11:6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic aciddimethylamide

[0160]

[0161] Compound 11 was prepared in a similar manner as described inExample 5.

[0162]¹H NMR (CDCl₃), δ (ppm): 3.12 (s, 6H), 3.88 (s, 3H), 3.90 (s, 6H),3.95 (s, 3H), 7.00 (dd, J=8.7, 2.4 Hz, 1H), 7.12 (s, 2H), 7.67 (s, 1H),8.17 (d, J=8.7 Hz, 1H),

[0163] MS (EI): m/z 413 (M+H).

EXAMPLE 12 Synthesis of Compound 12:1-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-3-phenyl-propenone

[0164]

[0165] Compound 12 was prepared in a similar manner as described inExample 5.

[0166]¹H NMR (CDCl₃), δ (ppm): 3.91 (s, 6H), 3.92 (s, 3H), 3.96 (s, 3H),7.04 (dd, J=8.7, 2.4 Hz, 1H), 7.14-7.20 (m, 3H), 7.41-7.47 (m, 3H),7.61-7.64 (m, 2H), 8.02-8.11 (m, 4H).

[0167] MS (EI): m/z 472 (M+H).

EXAMPLE 13 Synthesis of Compound 13:6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acid phenylester

[0168]

[0169] Compound 13 was prepared in a similar maimer as described inExample 5.

[0170]¹H NMR (CDCl₃), δ (ppm): 3.88 (s, 3H), 3.91 (s, 6H), 3.95 (s, 3H),7.05 (dd, J=8.9, 2.1 Hz, 1H), 7.18 (s, 2H), 7.28-7.37 (m, 3H0, 7.46-7.51(m, 2H), 7.83 (d, J=2.1 Hz, 1H), 8.14 (s, 1H), 8.15 (d, J=9.0 Hz, 1H).

[0171] MS (EI): m/z 462 (M+H).

EXAMPLE 14 Synthesis of Compound 14:[1-(5-dimethylamino-napihthalene-1-sulfonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0172]

[0173] Compound 14 was prepared in a similar manner as described inExample 5.

[0174]¹H NMR (CDCl₃), δ (ppm): 2.83 (s, 6H), 3.81 (s, 3H), 3.90 (s, 6H),3.97 (s, 3H), 6.95 (dd, J=8.9, 2.4 Hz, 1H), 7.13 (s, 2H), 7.16 (s, 1H),7.30 (d, J=2.1 Hz, 1H), 7.48-7.55 (m, 2H), 8.10 (d, J=9.0 Hz, 1H), 8.14(s, 1H), 8.22-8.31 (m, 2H), 8.60 (d, J=8.7 Hz, 1H).

[0175] MS (EI): m/z 575 (M+H).

EXAMPLE 15 Synthesis of Compound 15:[1-(2-dimethylamino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0176]

[0177] Compound 15 was prepared in a similar manner as described inExample 3.

[0178]¹H NMR (CDCl₃), δ (ppm): 2.30 (s, 6H), 2.75 (t, J=6.3 Hz, 2H),3.89 (s, 9H), 3.92 (s, 3H), 4.22 (t, J=6.6 Hz, 2H), 6.86 (d, J=2.4 Hz,1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 7.10 (s, 2H), 7.62 (s, 1H), 8.25 (d,J=9.0 Hz, 1H).

[0179] MS (EI): m/z 413 (M+H).

EXAMPLE 16 Synthesis of Compound 16:(6-methoxy-1-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0180]

[0181] Compound 16 was prepared in a similar manner as described inExample 3.

[0182]¹H NMR (CDCl₃), δ (ppm): 3.79 (s, 3H), 3.88 (s, 9H), 3.92 (s, 3H),6.80 (d, J=2.1 Hz, 1H), 6.95 (dd, J=9.0, 2.4 Hz, 1H), 7.07 (s, 2H), 7.47(s, 1H), 8.23 (d, J=9.0 Hz, 1H).

[0183] MS (EI): m/z 356 (M+H).

EXAMPLE 17 Synthesis of Compound 17:[1-(2-amino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0184]

[0185] Compound 17 was prepared in a similar manner as described inExample 3.

[0186]¹H NMR (CDCl₃), δ (ppm): 1.93 (br, 2H, NH₂), 3.15 (br, 2H), 3.89(s, 9H), 3.90 (s, 3H), 4.19 (t, J=5.1 Hz, 2H), 6.85 (d, J=2.1 Hz, 1H),6.94 (dd, J=8.7, 2.1 Hz, 1H), 7.07 (s, 2H), 7.62 (s, 1H), 8.21 (d, J=8.4Hz, 1H).

[0187] MS (EI): m/z 385 (M+H).

EXAMPLE 18 Synthesis of Compound 18:[1-(furan-2-carbonyl)-6-methoxy-1H-indol-3yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0188]

[0189] Compound 18 was prepared in a similar manner as described inExample 5.

[0190]¹H NMR (CDCl₃), δ (ppm): 3.91 (s, 9H), 3.94 (s, 3H), 6.67 (dd,J=3.6, 1.8 Hz, 1H), 7.06 (dd, J=8.7, 2.1 Hz, 1H), 7.20 (s, 2H), 7.52(dd, J=3.6, 0.9 Hz, 1H), 7.67 (dd, J=1.8, 0.9 Hz, 1H0, 8.05 (d, J=2.4Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.45 (s, 1H).

[0191] MS (EI): m/z 436 (M+H).

EXAMPLE 19 Synthesis of Compound 19:(1-ethyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0192]

[0193] Compound 19 was prepared in a similar manner as described inExample 3.

[0194]¹H NMR (CDCl₃), δ (ppm): 1.49 (t, J=7.2 Hz, 3H), 3.88 (s, 9H),3.91 (s, 3H), 4.15 (q, J=7.5 Hz, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.95 (dd,J=9.0, 2.4 Hz, 1H), 7.07 (s, 2H), 7.54 (s, 1H), 8.22 (d, J=9.0 Hz, 1H).

[0195] MS (EI): m/z 370 (M+H).

EXAMPLE 20 Synthesis of Compound 20:[6-methoxy-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0196]

[0197] Compound 20 was prepared in a similar manner as described inExample 3.

[0198]¹H NMR (CDCl₃), δ (ppm): 2.48 (t, J=4.2 Hz, 4H), 2.79 (t, J=6.6Hz, 2H), 3.66 (t, J=4.5 Hz, 4H), 3.87 (s, 9H), 3.91 (s, 3H), 4.22 (t,J=6.6 Hz, 2H), 6.85 (d, J=2.1 Hz, 1H), 6.95 (dd, J=8.7, 2.4 Hz, 1H),7.07 (s, 2H), 7.58 (s, 1H), 8.21 (d, J=9.0 Hz, 1H).

[0199] MS (EI): m/z 455 (M+H).

EXAMPLE 21 Synthesis of Compound 21:[1-(4-chloro-benzyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0200]

[0201] Compound 21 was prepared in a similar manner as described inExample 3.

[0202]¹H NMR (CDCl₃), δ (ppm): 3.80 (s, 3H), 3.81 (s, 6H), 3.89 (s, 3H),5.24 (s, 2H), 6.73 (d, J=2.1 Hz, 1H), 6.95 (dd, J=8.7, 2.1 Hz, 1H), 7.03(s, 2H), 7.06 (d, J=6.9 Hz. 2H), 7.26 (d, J=6.6 Hz, 2H), 7.49 (s, 1H),8.24 (d, J=8.7 Hz, 1H).

[0203] MS (EI): m/z 466 (M+H).

EXAMPLE 22 Synthesis of Compound 22:(1-benzyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0204]

[0205] Compound 22 was prepared in a similar manner as described inExample 3.

[0206]¹H NMR (CDCl₃), δ (ppm): 3.82 (s, 9H), 3.90 (s, 3H), 5.28 (s, 2H),6.80 (d, J=2.1 Hz, 1H), 6.98 (dd, J=8.7, 2.1 Hz, 1H), 7.05 (s, 2H), 7.18(m, 2H), 7.32 (m, 3H), 7.50 (s, 1H), 8.27 (d, J=9.0 Hz, 1H).

[0207] MS (EI): m/z 432 (M+H).

EXAMPLE 23 Synthesis of Compound 23:(6-fluoro-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0208]

[0209] Compound 23 was prepared in a similar manner as described inExample 1.

[0210]¹H NMR (CDCl₃), δ (ppm): 3.74 (s, 3H), 3.84 (s, 6H), 7.06-7.13 (m,3H), 7.28 (dd, J=9.6, 2.4 Hz, 1H), 8.10 (s, 1H), 8.19-8.23 (m, 1H),12.06 (br, 1H, NH).

[0211] MS (EI): m/z 330 (M+H).

EXAMPLE 24 Synthesis of Compound 24:(6-bromo-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0212]

[0213] Compound 24 was prepared in a similar manner as described inExample 1.

[0214]¹H NMR (CDCl₃), δ (ppm): 3.73 (s, 3H), 3.86 (s, 6H), 7.09 (s, 2H),7.38 (dd, J=8.4, 1.8 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 8.14 (s, 1H), 8.17(d, J=8.4 Hz, 1H), 12.13 (br, 1H, NH).

[0215] MS (EI): m/z 390 (M+H).

EXAMPLE 25 Synthesis of Compound 25:(4,5,6-trimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0216]

[0217] Compound 25 was prepared in a similar manner as described inExample 1.

[0218]¹H NMR (CDCl₃), δ (ppm): 3.72 (s, 3H), 3.76 (s, 6H), 3.78 (s, 6H),3.83 (s, 3H), 6.82 (s, 1H), 7.10 (s, 2H), 7.67 (d, J=3.0 Hz, 1H), 11.69(br, 1H, NH).

[0219] MS (EI): m/z 402 (M+H).

EXAMPLE 26 Synthesis of Compound 26:6-methoxy-3-(3,4,5-trimethoxy-benzyl)-1H-indole

[0220]

[0221] To a stirred solution of(6-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone(Compound 1) (90 mg, 0.26 mmol) and NaBH₄ (98 mg, 2.6 mmol) in ethanol(10 mL) was heated to reflux. After 24 h, the reaction mixture wasquenched by H₂O at 0° C. and extracted by CH₂Cl₂ (10 mL×3). The combinedorganic layer was dried by MgSO₄, then chromatographed under theconditions (EA: n-hexane=1:2) to afford Compound 26 as a colorless oil.

[0222]¹H NMR (CDCl₃), δ (ppm): 3.79(s, 9), 3.83 (s 3H), 4.02 (s, 2H),6.52 (s, 2H), 6.77 (dd, J=8.7, 2.1 Hz, 1H), 6,81 (s, 1H), 6.84 (d, J=2.1Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 8.03 (br, 1H, NH).

[0223] MS (EI): m/z 328 (M+H).

EXAMPLE 27 Synthesis of Compound 27:(5-methoxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0224]

[0225] To a solution of 5-methoxyindole (1 g, 6.79 mmol) in THF (30 mL)was added NaO^(t)Bu (0.98 g, 10.19 mmol) and stirred at room temperaturefor 15 min. 3,4,5-trimethoxybenzoyl chloride (2.35 g, 10.19 mmol) wasadded to the reaction mixture in one portion. After 15 hr, it wasevaporated, and the residue was extracted with CH₂Cl₂ (20 mL×3). Thecombined extracts were dried by MgSO₄ and evaporated to give a yellowoil which was chromatographed by silica gel (EtOAc:n-hexane=1:3) toafford Compound 26 (2.03 g, 88%) as a pale white solid.

[0226]¹H NMR (CDCl₃), δ (ppm): 3.91 (s, 9H), 3.94 (s, 3H), 6.56 (d,J=3.6 Hz, 1H), 6.95 (s, 2H), 7.00 (m, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.34(d, J=3.6 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H).

[0227] MS (EI): m/z 342 (M+H).

EXAMPLE 28 Synthesis of Compound 28:(6-fluoro-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0228]

[0229] Compound 28 was prepared in a similar manner as described inExample 27.

[0230]¹H NMR (CDCl₃), δ (ppm): 3.90 (s, 6H), 3.96 (s, 3H), 6.60 (dd,J=3.6, 0.6 Hz, 1H), 6.98 (s, 2H), 7.05-7.12 (m, 1H), 7.37 (d, J=3.9 Hz,1H), 7.51-7.55(m, 1H), 8.14 (dd, J=10.2, 2.4 Hz, 1H).

[0231] MS (EI): m/z 330 (M+H).

EXAMPLE 29 Synthesis of Compound 29:(5,6-dimethoxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0232]

[0233] Compound 29 was prepared in a similar manner as described inExample 27.

[0234]¹H NMR (CDCl₃), δ (ppm): 3.88 (s, 6H), 3.92 (s, 3H), 3.94 (s, 3H),3.96 (s, 3H), 6.51 (d, J=3.6 Hz, 1H), 6.96 (s, 2H), 7.07 (s, 1H), 7.22(d, J=3.6 Hz, 1H), 8.03 (s, 1H).

[0235] MS (EI): m/z 372 (M+H).

EXAMPLE 30 Synthesis of Compound 30:(5,6-bis-benzyloxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0236]

[0237] Compound 30 was prepared in a similar manner as described inExample 27.

[0238]¹H NMR (CDCl₃), δ (ppm): 3.89 (s, 6H), 3.95 (s, 3H), 5.22 (s, 2H),5.26 (s, 2H), 6.48 (d, J=3.9 Hz, 1H), 6.96 (s, 2H), 7.12 (s, 1H), 7.22(d, J=3.6 Hz, 1H), 7.31-7.40 (m, 6H), 7.47-7.54 (m, 4H), 8.14 (s, 1H).

[0239] MS (EI): m/z 524 (M+H).

EXAMPLE 31 Synthesis of Compound 31:[1,3]dioxolo[4,5-f]indol-5-yl-(3,4,5-trimethoxy-phenyl)-methanone

[0240]

[0241] Compound 31 was prepared in a similar manner as described inExample 27.

[0242]¹H NMR (CDCl₃), δ (ppm): 3.93 (s, 6H), 3.94 (s, 3H), 6.02 (s, 2H),6.49 (d, J=3.6 Hz, 1H), 6.97 (m, 3H), 7.23 (d, J=3.9 Hz, 1H), 7.96 (s,1H).

[0243] MS (EI): m/z 356 (M+H).

EXAMPLE 32 Synthesis of Compound 32:[3-(2-dimethylamino-ethyl)-5-methoxy-indol-1-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0244]

[0245] Compound 32 was prepared in a similar manner as described inExample 27.

[0246]¹H NMR (CDCl₃), δ (ppm): 2.5 (s, 6H), 2.86-2.95 (m, 4H), 3.83 (s,9H), 3.87 (s, 3H), 6.88 (s, 2H), 6.89-6.92 (m, 1H), 7.04 (d, J=2.4 Hz,1H), 7.14 (s, 1H), 8.14 (d, J=9.0 Hz, 1H), 9.25 (br, 1H, NH).

[0247] MS (EI): m/z 413 (M+H).

EXAMPLE 33 Synthesis of Compound 33:N-{2-[5-Methoxy-1-(3,4,5-trimethoxy-benzoyl)-1H-indol-3-yl]-ethyl}-acetamide

[0248]

[0249] Compound 33 was prepared in a similar manner as described inExample 27.

[0250]¹H NMR (CDCl₃), δ (ppm): 1.92 (s, 3H), 2.86 (t, J=7.2Hz, 2H), 3.52(dd, J=6.6, 13.2 Hz, 2H), 3.86 (s, 9H), 3.93 (s, 3H), 5.84 (br, 1H, NH),6.97 (dd, J=9.0, 2.4 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 8.18 (d, J=9.0 Hz,1H).

[0251] MS (EI): m/z 427 (M+H).

EXAMPLE 34 Synthesis of Compound 34:(5,6-dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0252]

[0253] Compound 34 was prepared in a similar manner as described inExample 1.

[0254]¹H NMR (CDCl₃), δ (ppm): 3.89 (s, 6H), 3.92 (s, 6H), 3.98 (s, 3H),6.93 (s, 1H), 7.11 (s, 2H), 7.59 (d, J=2.7 Hz, 1H), 7.91 (s, 1H), 8.72(s, 1H).

[0255] MS(EI): m/z 372 (M+H).

EXAMPLE 35 Synthesis of Compound 35:(5-methoxy-2-methyl-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0256]

[0257] Compound 35 was prepared in a similar manner as described inExample 27.

[0258]¹H NMR (CDCl₃), δ (ppm): 2.41 (s, 3H), 3.80 (s, 9H), 3.93 (s, 3H),6.34 (t, J=0.9 Hz, 1H), 6.65 (dd, J=9, 2.4 Hz, 1H), 6.92 (d, J=2.7 Hz,1H), 6.95 (s, 2H), 6.97 (d, J=8.7 Hz, 1H).

[0259] MS(EI): m/z 356(M+H).

EXAMPLE 36 Synthesis of Compound 36:(1,6-dimethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0260]

[0261] Compound 36 was prepared in a similar manner as described inExample 16.

[0262]¹H NMR (CDCl₃), δ (ppm): 2.52 (s, 3H), 3.82 (2, 3H), 3.89 (s, 6H),3.93 (s, 3H), 7.08 (s, 2H), 7.18˜7.15 (m, 2H), 7.52 (s, 1H), 8.23 (d,J=8.7 Hz, 1H).

[0263] MS(EI): m/z 340 (M+H).

EXAMPLE 37 Synthesis of Compound 37:(1-ethyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0264]

[0265] Compound 37 was prepared in a similar manner as described inExample 36.

[0266]¹H NMR (CDCl₃), δ (ppm): 1.52 (t, J=7.3 Hz, 3H), 2.53 (s, 3H),3.90 (s, 6H), 3.93 (s, 3H), 4.20 (q, J=7.3 Hz, 2H), 7.10 (s, 1H), 7.17(d, J=8.4 Hz), 7.20 (s, 1H), 7.60 (s, 1H), 8.23 (d, J=8.1 Hz, 1H).

[0267] MS(EI): m/z 354 (M+H).

EXAMPLE 38. Synthesis of Compound 38:(1-allyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0268]

[0269] Compound 38 was prepared in a similar manner as described inExample 4.

[0270]¹H NMR (CDCl₃), δ (ppm): 2.51 (s, 3H), 3.89 (s, 6H), 3.93 (s, 3H),4.75 (dt, J=5.4, 1.5 Hz, 2H), 5.26 (dt, J=5.4, 1.5 Hz, 2H), 5.174 (dd,J=17.1, 0.9 Hz, 1H), 5.29 (dd, J=10.5, 1.2 Hz, 1H), 7.10 (s, 2H),7.18˜7.15 (m, 2H), 7.57 (s, 1H), 8.24 (d, J=8.4 Hz, 1H).

[0271] MS(EI): m/z 366 (M+H).

EXAMPLE 39 Synthesis of Compound 39:(5-ethyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5trimethoxy-phenyl)-methanone

[0272]

[0273] Compound 39 was prepared in a similar manner as described inExample 37.

[0274]¹H NMR (CDCl₃), δ (ppm): 1.47 (t, J=7.3 Hz, 3H), 3.90 (s, 6H),3.93 (s, 3H), 4.132 (q, J=7.3Hz, 2H), 6.84 (s, 1H), 6.00 (s, 2H), 7.08(s, 2H), 7.50 (s, 1H), 7.84 (s, 1H).

[0275] MS(EI): m/z 384 (M+H).

Example 40 Synthesis of Compound 40:(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0276]

[0277] Compound 40 was prepared in a similar manner as described inExample 36.

[0278]¹H NMR (CDCI₃), δ (ppm): 3.78 (s, 3H), 3.90 (s, 6H), 3.93 (s, 3H),6.01 (s, 2H), 6.81 (d, J=0.5 Hz, 1H), 7.07 (s, 2H), 7.43 (s, 1H), 7.83(d, J=1 Hz, 1H).

[0279] MS(EI): m/z 370 (M+H).

Example 41 Synthesis of Compound 41:(5-allyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0280]

[0281] Compound 41 was prepared in a similar manner as described inExample 38.

[0282]¹H NMR (CDCl₃), δ (ppm): 3.90 (s, 6H), 3.93 (s, 3H), 4.69 (dt,J=5.4, 1.5 Hz, 2H), 5.15 (dd, J=17, 0.9 Hz, 1H), 5.29 (dd, J=9, 0.9 Hz,1H), 6.03˜5.94 (m , 3H), 7.68 (d, J=1 Hz, 1H), 7.08 (s, 2H), 7.48 (s,1H), 7.84 (d, J=1 Hz, 1H).

[0283] MS(EI): m/z 396 (M+H).

Example 42 Synthesis of Compound 42:(6-methoxy-2-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0284]

[0285] Compound 42 was prepared in a similar manner as described inExample 1.

[0286]¹H NMR (CDCl₃), δ (ppm): 2.52 (s, 3H), 3.80 (s, 9H), 3.91 (s, 3H),6.73 (dd, J=8.7, 2.1 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H), 7.05 (s, 2H), 7.35(d, J=8.7 Hz, 1H), 8.50 (s, 1H).

[0287] MS(EI): m/z 356 (M+H).

EXAMPLE 43 Synthesis of Compound 43:6-methoxy-3-(3,4,5-trimethoxy-phenylsulfanyl)-1H-indole

[0288]

[0289] Compound 43 was prepared in a similar manner as described inExample 36.

[0290]¹H NMR (CDCl₃), δ (ppm): 3.66 (s, 3H), 3.76 (s, 6H), 3.85 (s, 3H),6.37 (s, 2H), 6.82 (dd, J=8.4, 2.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 7.37(d, J=2.4 Hz, 1H); 7.47 (d, J=8.4 Hz, 1H), 8.29 (s, 1H).

[0291] MS(EI): m/z 346 (M+H).

EXAMPLE 44 Synthesis of Compound 44:(6-ethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0292]

[0293] Compound 44 was prepared in a similar manner as described inExample 1.

[0294]¹H NMR (CDCl₃), δ (ppm): 1.47 (t, J=7 Hz, 3H), 3.9 (s, 6H), 3.92(s, 3H), 4.09 (q, J=6.9 Hz, 2H), 6.92 (d, J=2.4 Hz, 1H), 6.99 (dd,J=8.7, 2.1 Hz, 1H), 7.12(s, 2H), 7.63 (d, J=2.7 Hz, 1H), 8.63 (br, 1H,NH).

[0295] MS(EI): m/z 356 (M+H).

Example 45 Synthesis of Compound 45:(7-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0296]

[0297] Compound 45 was prepared in a similar manner as described inExample 1.

[0298]¹H NMR (CDCl₃), δ (ppm): 3.90(s, 6H), 3.94(s, 3H), 3.99(s, 3H),6.78(d, J=7.8 Hz, 2H), 7.13(s, 2H), 7.26 (d, J=7.8 Hz, 1H), 7.71 (d, J=3Hz, 1H), 7.93(d, J=8.1, 1H), 8.96 (br, 1H, NH).

[0299] MS(EI): m/z 342 (M+H).

EXAMPLE 46 Synthesis of Compound 46:(4-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0300]

[0301] Compound 46 was prepared in a similar manner as described inExample 1.

[0302]¹H NMR (CDCl₃), δ (ppm): 3.79(s, 6H), 3.85(s, 3H), 3.94(s, 3H),6.66(d, J=7.8 Hz, 1H), 7.08(d, J=8.1 Hz, 1H), 7.19(s, 2H), 7.23(d, J=8.1Hz, 1H), 7.54(d, J=8.1 Hz, 1H), 8.71(br, 1H, NH).

[0303] MS(EI): m/z 342 (M+H).

EXAMPLE 47 Synthesis of Compound 47:(5-Methoxy-4-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0304]

[0305] Compound 47 was prepared in a similar manner as described inExample 1.

[0306]¹H NMR (CDCl₃), δ (ppm): 2.56 (s, 3H), 3.87 (s, 6H), 3.95 (s, 3H),6.99 (d, J=8.7 Hz, 1H), 7.19 (s, 2H), 7.22 (d, J=9.3 Hz, 1H), 7.43 (d,J=3 Hz, 1H), 9.10 (br, 1H, NH).

[0307] MS(EI): m/z 356 (M+H).

EXAMPLE48 Synthesis of Compound 48:(4,7-dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0308]

[0309] Compound 48 was prepared in a similar manner as described inExample 1.

[0310]¹H NMR (CDCl₃), δ (ppm): 3.74 (s, 3H), 3.84 (s, 6H), 3.93 (s, 3H),3.94 (s, 3H), 6.51 (d, J=8.4, 1H), 6.64 (d, J=8.4, 1H), 7.17 (s, 2H),7.53 (d, J=2.7 Hz, 1H), 9.00 (br, 1H, NH).

[0311] MS(EI): m/z 372 (M+H).

EXAMPLE 49 Synthesis of Compound 49:(4,6-dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0312]

[0313] Compound 49 was prepared in a similar manner as described inExample 1.

[0314]¹H NMR (CDCl₃), δ (ppm): 3.79 (s, 3H), 3.85 (s, 3H), 3.86(s, 6H),3.94 (s, 3H), 6.33 (d, J=2.1 Hz, 1H), 6.55 (d, J=1.8 Hz, 1H), 7.17(s,2H), 7.45 (d, J=2.7 Hz, 1H), 9.17 (br, 1H, NH).

[0315] MS(EI): m/z 372 (M+H).

EXAMPLE 50 Synthesis of Compound 50:(5,7-dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0316]

[0317] Compound 50 was prepared in a similar manner as described inExample 1.

[0318]¹H NMR (CDCl₃), δ (ppm): 3.85˜3.97 (m, 15H), 6.46 (d, J=2.1 Hz,1H), 7.48 (d, J=2.1 Hz, 1H), 7.65 (d, J=3.3 Hz, 1H ), 8.79 (br, 1H, NH).

[0319] MS(EI): m/z 372 (M+H).

EXAMPLE 51 Synthesis of Compound 51:{6-methoxy-1-[4-(4-nitro-phenyl)-furan-2-ylmethyl]-1H-indol-3-yl}-(3,4,5-trimethoxy-phenyl)-methanone

[0320]

[0321] Compound 51 was prepared in a similar manner as described inExample 9.

[0322]¹H NMR (CDCl₃), δ (ppm): 3.90 (s, 6H), 3.93 (s, 3H), 5.50 (s, 2H),6.45 (s, 1H), 6.87 (d, J=1.8 Hz, 1H), 7.01 (dd, J=8.7, 2.1 Hz, 1H), 7.11(s, 2H), 7.66 (s, 1H), 7.89 (dd, J=6.6, 2.0 Hz, 1H), 8.27 (dd, J=6.5,2.0 Hz, 1H), 9.08 (br, 1H, NH).

[0323] MS (EI): m/z 541 (M+H).

EXAMPLE 52 Synthesis of Compound 52:(6-hydroxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone

[0324]

[0325] Compound 52 was prepared in a similar manner as described inExample 1.

[0326]¹H NMR (CDCl₃), δ (ppm): 3.87 (s, 3H), 3.88 (s, 6H), 6.80 (dd,J=8.4, 2.1 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 7.08 (s, 2H), 7.65 (d, J=4.2Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 8.95 (br, 1H).

[0327] MS (EI): m/z 328 (M+H).

EXAMPLE 53 Synthesis of Compound 53:6-methoxy-3-(3,4,5-trimethoxy-benzenesulfonyl)-1H-indole

[0328]

[0329] Compound 53 was prepared in a similar manner as described inExample 43.

[0330]¹H NMR (CDCl₃), δ (ppm): 3.77(s, 3H), 3.83(s, 3H), 3.86(s, 6H),6.85(d, J=2.1 Hz, 1H), 6.89(dd, J=8.7, 1.5Hz, 1H), 7.25(s, 1H), 7.72(d,J=2.4Hz, 1H), 7.76(d, J=8.7 Hz, 1H), 9.11(br, s, 1H).

[0331] MS(EI): m/z 378 (M+H).

EXAMPLE 54 Synthesis of Compound 54:[1-(2-dimethylamino-ethyl)-4,5,6-trimethoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone

[0332]

[0333] Compound 54 was prepared in a similar manner as described inExample 15.

[0334]¹H NMR (CDCl₃), δ (ppm): 2.29(s, 6H), 2.70(t, J=6.8Hz, 2H),3,87(s, 6H), 3.89(s, 3H), 3.92(s, 3H), 3.94(s, 3H), 3.94(s, 3H), 4.15(t,J=6.8 Hz, 2H), 6.62(s, 1H), 7.15(s, 1H), 7.41 (s, 3H).

[0335] MS(EI): m/z 473 (M+H).

EXAMPLE 55 In Vitro Assays

[0336] Cell Growth Inhibition Assay: MCF-7 breast carcinoma cells weremaintained in plastic dishes in DMEM medium supplemented with 10% fetalbovine serum. For in vitro treatment, tumor cells were seeded in 100 mLof culture medium/well in 96-well plates to a final cell density of6×10³ cell/mL and incubated in a CO₂ incubator at 37° C. for 24 h. Thecells were treated with at least five different concentrations of a testindole compound, and incubated in a CO₂ incubator at 37° C. for 72 h.The number of viable cells was estimated using MTS assay and absorbancewas measured at 490 nm. Cytotoxicity of the test compounds was expressedin terms of IC₅₀ values. The values presented represent averages ofthree independent experiments, each with duplicate samples.

[0337] In addition, indole compounds described in the “Summary” sectionwere also test on HT-29 colon carcinoma cell line, as well as Hepa-G2hepatic cell line. At least 28 compounds have IC₅₀ values of at least 5μM. Unexpectedly, some of the test compounds have IC₅₀ values as lowas<10 nM.

[0338] Tubulin Polymerization Assay: Turbidimetric assays of microtubulewere performed as described by Lopes et al. (1997, Cancer Chemother.Pharmacol. 41: 37-47) and manual of Cytoskeleton with some modification.MAP-rich tubulin (2 mg/ml) was preincubated in polymerization buffer(0.1 M PIPES, pH 6.9, 1 mM MgCl₂) with drug at 4° C. for 2 min beforethe addition of 1 mM GTP. The samples were then rapidly warmed to 37° C.in a 96-well plate thermostatically controlled spectrophotometer andmeasuring the change at 350 nm with time. Results show that a testindole compound of 2 μM inhibited tubulin polymerization.

[0339] Cell Growth Inhibition Assay on Multiple-drug Resistant HumanCancer Lines: Indole compounds were tested against several panels ofdrug-resistant cell lines. It is well known that several anti-mitoticagents, including vinca alkaloid (vincristine, vinblastine) and taxol,have been introduced in clinic to treat various human cancers. Vincaalkaloid resistance has been attributed to a number of mechanismsassociated with multi-drug resistance (MDR) phenotype includingoverexpression of p-glycoprotein and the multi-drug resistant-associatedprotein (MRP). The mechanisms responsible for taxol resistance includeoverexpression of p-glycoprotein and mutation of tubulin. Forcomparison, three anti-mitotic agents, i.e., Vincristine, VP-16,Cisplatin, CPT (camptothecin), and Taxol (paclitaxel) were also testedagainst several panels of drug-resistant cell lines.

[0340] KB-Vin10, a vincristine-resistant cell line derived from itsparental cell line KB, showed over expression of p-glycoprotein.HONECis-6, derived from cell line HONE-1, showed resistant to analkylating agent such as cisplatin. The mechanism of thecisplatin-resistance is under investigation. KB100, i.e., camptotnecin(CPT)-resistant cell line, displayed down regulation of topoisomerase Iand an undefined mechanism responsible for drug resistance. Themechanisms responsible for VP16-resistance (KB7D) were down-regulationof topoisomerase II and overexpression of MRP 1. CPT30, a CPT-resistantcell line showed quantitatively and qualitative change oftopoisomerase 1. KBtaxol-5 showed mutation of tubulin.

[0341] The results shown in Table 1 indicate that indole compoundsdescribed in the “Summary” section are strong anti-mitotic agents, andare useful in treatment of various multiple-drug resistant cancers.TABLE 1 Cytotoxicity of indole compounds against various human cancerresistant cell lines (nM) KB HONE HINECis KBtaxol Cell Line KB −Vin10 −1−6 KB100 KB100R KB7D KB7DR −5 Vin. Cis CPT Reverse VI-16 Reverse TaxolCell type Oral Res NPC Res. Res CPT Res Res. VP-16 Res. Res. Compound 16 7 4 4.5 8 12 4 6 7 Compound 6 13 9.6 19 19 18 18 8 15 37 Compound 2794 85 40 40 83 81 41 46 100 Vincristine 1 43 0.5 0.6 1920 337 VP-16 50044000 3500 Cisplatin 3 5 3000 15000 CPT 26 400 1286 133 Taxol 10 80

EXAMPLE 56 In Vivo Assay

[0342] CAM Assay for Antiangiogenic Potency: Test compounds weredissolved in a 2.5% aqueous agarose solution (final concentration: 1-20mg/mL). For the preparation of the pellets, 10 μL of these solutionswere applied dropwise on circular Teflon supports of 3 mm in diameterand then cooled to room temperature at once. After incubation at 37° C.and relative humidity of 80% for 65-70 h, the fertilized hens' eggs werepositioned in a horizontal position and rotated several times. Beforethe opening on the snub side, 10 mL of albumin were aspirated from ahole on the pointed side. At two-third of the height (from the pointedside), the eggs were traced with a scalpel, and the shells were removedwith forceps. The aperture (cavity) was covered with keep-fresh film,and the eggs were incubated at 37° C. at a relative humidity of 80% for75 h. When the formed chorioallantoic membrane (CAM) had approximately adiameter of 2 cm, one pellet (1 pellet/egg) was placed on it. The eggswere incubated for 1 day and subsequently evaluated under thestereomicroscope. Three compounds were tested, and all showanti-angiogenesis activities.

Other Embodiments

[0343] All of the features disclosed in this specification may becombined in any combination. Each feature disclosed in thisspecification may be replaced by an alternative feature serving thesame, equivalent, or similar purpose. Thus, unless expressly statedotherwise, each feature disclosed is only an example of a generic seriesof equivalent or similar features.

[0344] From the above description, one skilled in the art can easilyascertain the essential characteristics of the present invention, andwithout departing from the spirit and scope thereof, can make variouschanges and modifications of the invention to adapt it to various usagesand conditions. For example, compounds structurally analogous the indolecompounds of this invention also can be made, screened for theiranti-cancer activities, and used to practice this invention. Thus, otherembodiments are also within the claims.

What is claimed is:
 1. A compound of the following formula:

wherein L₁ is C(O); L₂ is a bond; R₁ is aryl or heteroaryl; R₂ is H,aryl, heteroaryl, halogen, nitro, nitroso, cyano, azide, isothionitro,OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′,NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)OR, or C(O)NRR′; each of R_(a), R_(b), R_(c), andR_(d), independently, is R, halogen, nitro, nitroso, cyano, azide,isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR,NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′, or R_(b) and R_(c), R_(a) andR_(b), or R_(c) and R_(d) taken together are O(CH₂)_(n)O; and R_(e) isH, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, halogen, nitro,nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′,SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′,NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′; inwhich each of R, R′, and R″, independently, is H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4,or
 5. 2. The compound of claim 1, wherein R₁ is 5, 6, or 7-member arylor heteroaryl tri-substituted with alkyloxy.
 3. The compound of claim 2,wherein R₁ is 3,4,5-trimethoxylphenyl.
 4. The compound of claim 1,wherein R_(e) is H or alkyl.
 5. The compound of claim 4, wherein R₁ is3,4,5-trimethoxylphenyl.
 6. The compound of claim 5, wherein each ofR_(a), R_(b), R_(c), and R_(d), independently, is H, alkyloxy, alkyl, orhalogen.
 7. The compound of claim 6, wherein R_(c) is alkyloxy, alkyl,or halogen, and each of R_(a), R_(b), and R_(d) is H.
 8. The compound ofclaim 7, wherein R₂ is H, OR, SO₂R, C(O)OR, or C(O)NRR′, in which eachof R and R′, independently, is H, alkyl, aryl, or heteroaryl.
 9. Thecompound of claim 5, wherein R_(b) and R_(c) taken together areO(CH₂)_(n)O, and each of R_(a) and R_(d) is H, in which n is 1 or
 2. 10.The compound of claim 1, wherein the compound is(6-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acidtert-butyl ester;(1-Methanesulfonyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic aciddimethylamide;6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acid phenylester;[1-(5-Dimethylamino-naphthalene-1-sulfonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(6-Fluoro-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Bromo-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(4,5,6-Trimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5,6-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methoxy-2-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Ethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(7-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(4-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Methoxy-4-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(4,7-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(4,6-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5,7-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Hydroxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;4-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-sulfonyl]-benzoicacid; and(5H-[1,3]Dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone.11. A compound of the following formula:

wherein L₁ is C(O); L₂ is a bond; R₁ is aryl or heteroaryl; R₂ is alkyl,alkenyl, alkynyl, cyclyl, or heterocyclyl; each of R_(a), R_(b), R_(c),and R_(d), independently, is R, halogen, nitro, isothionitro, OR,OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRSO₂NR′R″,NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R,C(O)OR, C(O)NRR′, or R_(b) and R_(c), R_(a) and R_(b), or R_(c), andR_(d) taken together are O(CH₂)_(n)O; and R_(e) is H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, halogen, nitro,nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′,SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′,NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′; inwhich each of R, R′, and R″, independently, is H, alkyl, alkenyl,alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4,or 5
 12. The compound of claim 11, wherein R₁ is 5, 6, or 7-member arylor heteroaryl tri-substituted with alkyloxy.
 13. The compound of claim12, wherein R₁ is 3,4,5-trimethoxylphenyl.
 14. The compound of claim 11,wherein R_(e) is H or alkyl.
 15. The compound of claim 14, wherein R₁ is3,4,5-trimethoxylphenyl.
 16. The compound of claim 15, wherein each ofR_(a), R_(b), R_(c), and R_(d), independently, is H, alkyloxy, alkyl, orhalogen.
 17. The compound of claim 16, wherein R_(c) is alkyloxy, alkyl,or halogen, and each of R_(a), R_(b), and R_(d) is H.
 18. The compoundof claim 17, wherein R₂ is alkyl, alkenyl, or alkynyl.
 19. The compoundof claim 15, wherein R_(b) and R_(c) taken together are O(CH₂)_(n)O, andeach of R_(a) and R_(d) is H, in which n is 1 or
 2. 20. The compound ofclaim 11, wherein the compound is(6-Methoxy-1-pyridin-4-ylmethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(1-Allyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[6-Methoxy-1-(2-piperidin-1-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methoxy-1-prop-2-ynyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[1-(2-Dimethylamino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methoxy-1-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[1-(2-Amino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(1-Ethyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[6-Methoxy-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;[1-(4-Chloro-benzyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(1-Benzyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(1,6-Dimethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(1-Ethyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(1-Allyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Ethyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Allyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;{6-Methoxy-1-[4-(4-nitro-phenyl)-furan-2-ylmethyl]-1H-indol-3-yl}-(3,4,5-trimethoxy-phenyl)-methanone;and[1-(2-Dimethylamino-ethyl)-4,5,6-trimethoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone.21. A compound of the following formula:

wherein L₁ is C(O); L₂ is a bond; R₁ is aryl or heteroaryl; R₂ is COR′″;each of R_(a), R_(b), R_(c,)and R_(d), independently, is R, halogen,nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR,OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′,NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′,or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) taken togetherare O(CH₂)_(n)O; and R_(e) is R, halogen, nitro, nitroso, cyano, azide,isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR,NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′; in which each of R, R′, and R″independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl,or heterocyclyl; R′″ is H, alkyl, alkenyl, alkynyl, heteroaryl, cyclyl,or heterocyclyl; and n is 1, 2, 3, 4, or
 5. 22. The compound of claim21, wherein R₁ is 5, 6, or 7-member aryl or heteroaryl tri-substitutedwith alkyloxy.
 23. The compound of claim 22, wherein R₁ is3,4,5-trimethoxylphenyl.
 24. The compound of claim 21, wherein R_(e) isH or alkyl.
 25. The compound of claim 24, wherein R₁ is3,4,5-trimethoxylphenyl.
 26. The compound of claim 25, wherein each ofR_(a), R_(b), R_(c), and R_(d), independently, is H, alkyloxy, alkyl, orhalogen.
 27. The compound of claim 26, wherein R_(c) is alkyloxy, alkyl,or halogen, and each of R_(a), R_(b), and R_(d) is H.
 28. The compoundof claim 27, wherein R′″ is alkyl, alkenyl, heterocyclyl, or heteroaryl.29. The compound of claim 21, wherein the compound is[6-Methoxy-1-pyridine-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;[6-Methoxy-1-(morpholine-4-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;1-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-3-phenyl-propenone;[1-(Furan-2-carbonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;{2-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-2-oxo-ethyl}-carbamicacid 9H-fluoren-9-yl-methyl ester;[6-Methoxy-1-pyridine-3-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;and[6-Methoxy-1-(thiophene-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone.30. A compound of the following formula:

wherein L₁ is a bond; L₂ is C(O); R₁ is H, alkenyl, alkynyl, aryl,heteroaryl, cyclyl, heterocyclyl, halogen, nitro, nitroso, cyano, azide,isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR,NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)OR, or C(O)NRR′; R₂ is aryl or heteroaryl; each ofR_(a), R_(b), R_(c), and R_(d), independently, is H, unsubstitutedalkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl,halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′, or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) takentogether are O(CH₂)_(n)O; and R_(e) is H, alkyl, alkenyl, alkynyl,cyclyl, heterocyclyl, heteroaryl, halogen, nitro, nitroso, cyano, azide,isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR,NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′,NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′; in which each of R, R′, and R″independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl,or heterocyclyl; and n is 1, 2, 3, 4, or
 5. 31. The compound of claim30, wherein R₂ is 5, 6, or 7-member aryl or heteroaryl tri-substitutedwith alkyloxy.
 32. The compound of claim 31, wherein R₂ is3,4,5-trimethoxylphenyl.
 33. The compound of claim 30, wherein R_(e) isH or alkyl.
 34. The compound of claim 33, wherein R₂ is3,4,5-trimethoxylphenyl.
 35. The compound of claim 34, wherein each ofR_(a), R_(b), R_(c), and R_(d), independently, is H, alkyloxy, alkyl, orhalogen.
 36. The compound of claim 35, wherein R_(b) is alkyloxy, alkyl,or halogen, and each of R_(a), R_(c), and R_(d) is H.
 37. The compoundof claim 36, wherein R₁ is H or alkyl.
 38. The compound of claim 34,wherein R_(b) and R_(c) taken together are O(CH₂)_(n)O, and each ofR_(a) and R_(d) is H, in which n is 1 or
 2. 39. The compound of claim33, wherein R₂ is 3,5-dimethoxylphenyl.
 40. The compound of claim 31,wherein the compound is(5-Methoxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Fluoro-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5,6-Dimethoxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5,6-Bis-benzyloxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[1,3]Dioxolo[4,5-f]indol-5-yl-(3,4,5-trimethoxy-phenyl)-methanone;[3-(2-Dimethylamino-ethyl)-5-methoxy-indol-1-yl]-(3,4,5-trimethoxy-phenyl)-methanone;N-{2-[5-Methoxy-1-(3,4,5-trimethoxy-benzoyl)-1H-indol-3-yl]-ethyl}-acetamide;(5-Methoxy-2-methyl-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Methyl-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone; and(3,5-Dimethoxy-phenyl)-(5-methoxy-indol-1-yl)-methanone.
 41. A compoundof the following formula:

wherein L₁ is O, S, NR, SO₂, or CH₂; L₂ is a bond; R₁ is 5, 6, or7-member aryl or heteroaryl tri-substituted with alkyloxy; and each ofR₂, R_(a), R_(b), R_(c), R_(d), and R_(e), independently, R, halogen,nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR,OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′,NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′,or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) taken togetherare O(CH₂)_(n)O; in which each of R, R′, and R″, independently, is H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; andn is 1, 2, 3, 4, or
 5. 42. The compound of claim 41, wherein R₁ is3,4,5-trimethoxylphenyl.
 43. The compound of claim 41, wherein R_(e) isH or alkyl.
 44. The compound of claim 43, wherein R₁ is3,4,5-trimethoxylphenyl.
 45. The compound of claim 44, wherein each ofR_(a), R_(b), R_(c), and R_(d), independently, is H, alkyloxy, alky, orhalogen.
 46. The compound of claim 45, wherein R_(c) is alkyloxy, alkyl,or halogen, and each of R_(a), R_(b), and R_(d) is H.
 47. The compoundof claim 44, wherein R_(b) and R_(c) taken together are O(CH₂)_(n)O, andeach of R_(a) and R_(d) is H, in which n is 1 or
 2. 48. The compound ofclaim 41, wherein the compound is6-Methoxy-3-(3,4,5-trimethoxy-benzyl)-1H-indole;6-Methoxy-3-(3,4,5-trimethoxy-phenylsulfanyl)-1H-indol; and6-Methoxy-3-(3,4,5-trimethoxy-benzenesulfonyl)-1H-indole.
 49. A compoundof the following formula:

wherein L₁ is a bond; L₂ is O, S, NR, SO₂, or CH₂; R₂ is 5, 6, or7-member aryl or heteroaryl tri-substituted with alkyloxy; and each ofR₁, R_(a), R_(b), R_(c), R_(d), and R_(e), independently, R, halogen,nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR,OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′,NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′,or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) taken togetherare O(CH₂)_(n)O; in which each of R, R′, and R″, independently, is H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; andn is 1, 2, 3, 4, or
 5. 50. The compound of claim 49, wherein R₂ is3,4,5-trimethoxylphenyl.
 51. The compound of claim 49, wherein R_(e) isH or alkyl.
 52. The compound of claim 51, wherein each of R_(a), R_(b),R_(c), and R_(d), independently, is H, alkyloxy, alkyl, or halogen. 53.The compound of claim 52, wherein R_(b) is alkyloxy, alkyl, or halogen,and each of R_(a), R_(c), and R_(d) is H.
 54. The compound of claim 51,wherein R_(b) and R_(c) taken together are O(CH₂)_(n)O, and each ofR_(a) and R_(d) is H, in which n is 1 or
 2. 55. A compound of thefollowing formula:

wherein L₁ is O, S, NR, SO₂, or CH₂; L₂ is a bond; R₁ is 5, 6, or7-member aryl or heteroaryl di-substituted with alkyloxy; and each ofR₂, R_(a), R_(b), R_(c), R_(d), and R_(e), independently, R, halogen,nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR,OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′,NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′,or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) taken togetherare O(CH₂)_(n)O; in which each of R, R′, and R″, independently, is H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; andn is 1, 2, 3, 4, or
 5. 56. The compound of claim 55, wherein R₁ is3,5-dimethoxylphenyl.
 57. A compound of the following formula:

wherein L₁ is a bond; L₂ is O, S, NR, SO₂, or CH₂; R₂ is 5, 6, or7-member aryl or heteroaryl di-substituted with alkyloxy; and each ofR₁, R_(a), R_(b), R_(c), R_(d), and R_(e), independently, R, halogen,nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR,OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′, NRSO₃R′,NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′,or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) taken togetherare O(CH₂)_(n)O; in which each of R, R′, and R″, independently, is H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; andn is 1, 2, 3, 4, or
 5. 58. The compound of claim 57, wherein R₂ is3,5-dimethoxylphenyl.
 59. A method for treating cancer, comprisingadministering to a subject in need thereof an effective amount of acompound of the following formula:

wherein each of L₁ and L₂, independently, is a bond, C(O), O, S, NR,SO₂, or CH₂; in which if one of L₁ and L₂ is a bond, the other one isC(O), O, S, NR, SO₂, or CH₂; each of R₁ and R₂, independently, is R,halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′; each of R_(a), R_(b), R_(c), R_(d) and R_(e), independently,R, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′, or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) takentogether are O(CH₂)_(n)O; and in which each of R, R′, and R″,independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl,or heterocyclyl; and n is 1, 2, 3, 4, or
 5. 60. The method of claim 59,wherein the compound is(6-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methoxy-1-pyridin-4-ylmethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(1-Allyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[6-Methoxy-1-(pyridine-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acidtert-butyl ester;(1-Methanesulfonyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[6-Methoxy-1-(morpholine-4-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;[6-Methoxy-1-(2-piperidin-1-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methoxy-1-prop-2-ynyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic aciddimethylamide;1-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-3-phenyl-propenone;6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acid phenylester;[1-(5-Dimethylamino-naphthalene-1-sulfonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;[1-(2-Dimethylamino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methoxy-1-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[1-(2-Amino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;[1-(Furan-2-carbonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(1-Ethyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[6-Methoxy-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;[1-(4-Chloro-benzyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(1-Benzyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Fluoro-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Bromo-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(4,5,6-Trimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;6-Methoxy-3-(3,4,5-trimethoxy-benzyl)-1H-indole;(5-Methoxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Fluoro-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5,6-Dimethoxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5,6-Bis-benzyloxy-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;[1,3]Dioxolo[4,5-f]indol-5-yl-(3,4,5-trimethoxy-phenyl)-methanone;[3-(2-Dimethylamino-ethyl)-5-methoxy-indol-1-yl]-(3,4,5-trimethoxy-phenyl)-methanone;N-{2-[5-Methoxy-1-(3,4,5-trimethoxy-benzoyl)-1H-indol-3-yl]-ethyl}-acetamide;(5,6-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Methoxy-2-methyl-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(1,6-Dimethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(1-Ethyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(1-Allyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Ethyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Allyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(6-Methoxy-2-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;6-Methoxy-3-(3,4,5-trimethoxy-phenylsulfanyl)-1H-indole;(6-Ethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(7-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(4-Methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5-Methoxy-4-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(4,7-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(4,6-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(5,7-Dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;{6-Methoxy-1-[4-(4-nitro-phenyl)-furan-2-ylmethyl]-1H-indol-3-yl}-(3,4,5-trimethoxy-phenyl)-methanone;(6-Hydroxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;6-Methoxy-3-(3,4,5-trimethoxy-benzenesulfonyl)-1H-indole;[1-(2-Dimethylamino-ethyl)-4,5,6-trimethoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;4-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-sulfonyl]-benzoicacid;(5H-[1,3]Dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;{2-[6-Methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-2-oxo-ethyl}-carbamicacid 9H-fluoren-9-yl-methyl ester;[6-Methoxy-1-(pyridine-3-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;[6-Methoxy-1-(thiophene-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;(5-Methyl-indol-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone; and(3,5-Dimethoxy-phenyl)-(5-methoxy-indol-1-yl)-methanone.
 61. A methodfor inhibiting tubulin polymerization, comprising administering to asubject in need thereof an effective amount of a compound of thefollowing formula:

wherein each of L₁ and L₂, independently, is a bond, C(O), O, S, NR,SO₂, or CH₂; in which if one of L₁ and L₂ is a bond, the other one isC(O), O, S, NR, SO₂, or CH₂; each of R₁ and R₂, independently, is R,halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′; each of R_(a), R_(b), R_(c), R_(d) and R_(e), independently,R, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′, or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) takentogether are O(CH₂)_(n)O; and in which each of R, R′, and R″,independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl,or heterocyclyl; and n is 1, 2, 3, 4, or
 5. 62. A method for treating anangiogenesis-related disorder, comprising administering to a subject inneed thereof an effective amount of a compound of the following formula:

wherein each of L₁ and L₂, independently, is a bond, C(O), O, S, NR,SO₂, or CH₂; in which if one of L₁ and L₂ is a bond, the other one isC(O), O, S, NR, SO₂, or CH₂; each of R₁ and R₂, independently, is R,halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′; each of R_(a), R_(b), R_(c), R_(d) and R_(e), independently,R, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R,OC(O)OR, OC(O)NRR′, SO₂R, SO₃R, SO₂NRR′, SR, NRR′, NRSO₂NR′R″, NRSO₂R′,NRSO₃R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR,C(O)NRR′, or R_(b) and R_(c), R_(a) and R_(b), or R_(c) and R_(d) takentogether are O(CH₂)_(n)O; and in which each of R, R′, and R″,independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl,or heterocyclyl; and n is 1, 2, 3, 4, or 5.